Conversely, alleles of <i>ABHD5</i> carrying point mutations associated with ichthyosis in humans failed to accelerate PNPLA1-mediated AcylCer biosynthesis.
Notably, topical application of epidermal lipids from wild-type onto Pnpla1-mutant mice promoted rebuilding of the corneocyte-bound lipid envelope, indicating that supplementation of ichthyotic skin with omega-O-acylceramides might be a therapeutic approach for the treatment of skin symptoms in individuals affected by omega-O-acylceramide deficiency.
Altogether, our results indicate that PNPLA1 is directly involved in acylceramide synthesis as a transacylase, and provide important insights into the molecular mechanisms of skin barrier formation and of ichthyosis pathogenesis.
The phenotype of the HID (hystrix-like ichthyosis, deafness)/KID (keratitis, ichthyosis, deafness) syndrome is primarily characterized by skin changes.
Mutations in connexin 26 are linked to diseases including Vohwinkel syndrome, keratitis-ichthyosis deafness, and hystrix-like ichthyosis deafness syndromes, palmoplantar keratoderma with deafness, deafness with Clouston-like phenotype, and Bart-Pumphrey syndrome.
In addition, whole exome sequencing approach also solved the genetics of some syndromic forms of PAI including IMAGe syndrome (<i>CDKN1C</i>), Irish traveler syndrome (<i>MCM4</i>), MIRAGE syndrome (<i>SAMD9</i>); and most recently a syndrome combining FGD with steroid-resistant nephrotic syndrome and ichthyosis caused by mutations in the gene for sphingosine-1-phosphate lyase 1 (<i>SGPL1</i>).
In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase.
The diagnosis of multiple sulfatase deficiency was demonstrated by measuring sulfatase activities in fresh leukocytes: there were large deficiencies of arylsulfatase A and B plus reduced arylsulfatase C. The ichthyosis associated with multiple sulfatase deficiency has an autosomal recessive inheritance, is caused by steroid sulfatase deficiency, and the scaling is sometimes milder than in X-linked recessive ichthyosis.
Clinically typical phenotype of the TGM1 mutation carrier includes large, thick, brownish scales, but ichthyosis of some of these patients tends to be milder.
The TGM1 mutation spectrum was characterised and genotype-phenotype correlations investigated in 104 patients with ARCI ascertained through the National Registry for Ichthyosis and Related Disorders in the USA.